Angiogenesis is known to occur not only in normal physiological events in human and animals such as embryogenesis or ovulation or placentation in the female sexual cycle, but also in repair processes such as wound healing and inflammation, and in various pathological events where rapidly grown and proliferated capillaries damage tissues seriously. Diseases due to such pathological growth of capillaries include diabetic retinopathy, retrolenticular fibroplasia, angiogenesis following kelatoplasty, glaucoma, ocular tumor and trachoma in ophthalmology, psoriasis and purulent granuloma in dermatology, hemangioma and fibrous hemangioma in pediatrics, hypertrophic scar and granulation in surgery, rheumatic arthritis and edematous sclerosis in internal medicine, atherosclerosis in heart diseases, and various tumors.
In particular, abnormally increased angiogenesis in diabetic retinopathy and trachoma causes loss of eye sight in many people, and abnormal angiogenesis in the joint may break cartilage in the joint, inflicting rheumatic arthritis on many patients. Circumstances being such, development of substances has been desired which are useful for treatment and prevention of such diseases accompanying abnormally increased angiogenesis.
And, rapid growth of tumor is considered to be a result of angiogenesis induced by angiogenitic factor produced by tumor cells. Because angiostatic agents are thus expected to be new therapeutic agents against various tumors, studies exploring such agents have started [J. Folkman; Advances in Cancer Research, 43 175, 1985, edited by George Klein and Sidney Weinhouse].
It has already been clarified that heparin or a heparin fragment combined with a so-called angiostatic steroid such as cortisone inhibits angiogenesis [J. Folkman et al.; Science, 221 719 (1983), J. Folkman et al.; Annals of Surgery, 206 375 (1987)].
It has also been reported that a collagen synthesis inhibitor such as L-azetidine-2-carboxylic acid or cis-hydroxyproline, and an inhibitor of collagen proline hydroxylase, or a collagen synthesis inhibitor in combination with .beta.-cyclodextrin-tetradecasulfate or heparin exerts an angiostatic effect [D. Ingber and J. Folkman; Laboratory Investigation, 59 44 (1988)].
And, it has been pointed out that basement membrane and collagen synthesis in the membrane play an important role in angiogenesis [M. E. Maragoudakis, M. Sarmonika and M. Panoutsacopoulous; J. Pharmacol. Exp. Ther. 244, 729 (1988), D. E. Ingber, J. A. Madri and J. Folkman; Endocrinology, 119, 1768 (1986)].
It has been recognized that fumagillin produced by Aspergillus fumigatus known hitherto as an antibiotic and antiprotozoal agent exerts strong angiostatic effect which is potentiated by combination with heparin or .beta.-cyclodextrin tetradecasulfate [J. Folkman and T. Kanamaru et al.; U.S. patent application Ser. No. 173305, filed on Mar. 25, 1988]. Besides, it has been reported that a steroidal hormone, medroxyprogesterone acetate, which was developed as a synthetic luteal hormone, inhibits angiogenesis induced by various tumors in evaluation of angiogenesis using rabbit corneal micropocket assay [Proceedings of the National Academy of Science, U.S.A 78 1176 (1991)]. And, also with prostaglandin synthesis inhibitors such as Indomethacin, diclofenac sodium, aspirin, etc. [Anticancer Research, 6 251 (1986)] and with anthracene-type anticancer agents such as mitoxantrone, bisantrene, etc. [Biochemical & Biophysical Research Communication, 140 901 (1986)], angiostatic activity is recognized.
And, it has recently been revealed that antirheumatics containing gold, such as gold sodium thiomalate, auranofin, etc. show angiostatic activity, suggesting that at least a part of the antirheumatic action of these compounds is due to their angiostatic action [Journal of Clinic Investigation, 79 1440 (1987), Biochemical & Biological Research Communication, 154 205 (1988)].
In addition to the afore-mentioned non-proteineous angiostatic agents, some proteineous angiostatic agents have been reported such as, cartilage derived factors [Science, 193 70 (1976)], protamine [Nature, 297 307 (1982)], factors derived from human retinal pigment epithelial cells [Arch. Ophthalmol. 103 1870 (1985)] and interferon [Cancer Research, 47 5155 (1987)]. But these are considered to be of little practical use as medicines.
While there have been several reports as described above concerning compounds showing angiostatic activity, the activity is considered to be insufficient for clinical use. Therefore, production of low-molecular and strong angiostatic agents which can be clinically used have been ardently desired.